Research on Depression Focuses on Brain Circuitry

Science experts are learning more about the linking of cranial regions as well as predicting which patients will respond to drugs

Judy Foreman

At McLean Hospital in Belmont, Mass., brain researchers have hit upon what could become a new way to treat depression--blocking a brain chemical called dynorphin, the "evil cousin" of endorphin, which triggers the "runner's high."

At UCLA, psychiatrists have modified the standard EEG (or electroencephalogram) to predict which depressed patients will get better with drugs and which won't--weeks before the patients can detect any changes in mood.

At the University of Toronto, scientists are tracing the specific components of depression--sadness, distorted thinking, disturbed sleep--to separate, but linked, regions of the brain. In the process, they've found one key region in the "emotional brain," area 24a. If that's overactive, depressed people improve with drug therapy; if it's not, they won't. At Beth Israel Deaconess Medical Center in Boston, researchers are trying yet another approach--transcranial magnetic stimulation--that uses magnets placed on the scalp to stimulate the prefrontal lobes of the brain, which are often sluggish in depression.

Depression, in other words, is no longer believed to be a mere deficiency of key brain chemicals--norepinephrine, dopamine and, perhaps most important, serotonin. Today, brain researchers view this common illness, which strikes about 19 million Americans, as a malfunction of particular circuits. Those circuits connect the limbic system, or "emotional brain," with the prefrontal cortex, or "thinking brain," and the brain stem and hypothalamus, which control basic functions such as sleep, appetite and libido.

In truth, there never was much proof that depression was merely a serotonin deficiency. That was an inference from data showing that people who are aggressive or suicidal often have low serotonin, says Dr. Peter Whybrow, director of the neuropsychiatric institute at UCLA. And from data showing that if researchers deprived people of tryptophan, a substance from which the body makes serotonin, they quickly got very depressed.

But now, despite the obvious efficacy of serotonin-boosting drugs such as Prozac, Zoloft and Paxil, it's clear that when a person is depressed, there's a lot more going wrong in specific areas of the brain than just low levels of serotonin.

The Human Brain's Electrical Signals

The brain works by chemical and electrical signals. When an electric current passes through one cell, the cell releases a neurotransmitter, which floats to the next cell, causing it to "fire up electrically." This process, repeated cell after cell, activates whole circuits in the brain, says Dr. Alvaro Pascual-Leone, director of the transcranial magnetic stimulation lab at Beth Israel.

While most drug developers have focused on the chemical side of the equation, he says, depression can also be treated by getting the electrical circuits back to normal. One way to do this is ECT, or electroconvulsive "shock" therapy, which causes a brain-wide seizure. ECT is effective, but it can cause confusion and memory loss.

A potentially better though still experimental approach, Pascual-Leone says, is transcranial magnetic stimulation, or TMS, which uses a magnetic field to kick-start just the prefrontal lobes. That, in turn, may affect the limbic system, potentially easing depression without brain-wide seizures and memory loss.

The hallmark of depression, brain mapping shows, is too little activity in the right and left prefrontal lobes (behind the eyes) and the right and left parietal lobes (on the side of the brain, toward the top), and too much activity in the limbic system, or emotional brain.

But the limbic system and prefrontal lobes, which govern thinking, are actually wired together through specific neural circuits, says Dr. Helen Mayberg, a professor of neurology and psychiatry at the University of Toronto. She uses PET scans to measure blood flow and map "depression circuits" in the brain.

The close links between the limbic system and prefrontal lobes probably explain why depressed people not only feel bad emotionally but also have trouble thinking. "For many people, yes, they are sad," she says. "But what brings a lot of people to the doctor is the fact that they can't think straight."

In addition to the abnormal activity in the entire limbic system and prefrontal lobes, scientists are finding changes in specific subregions when people are depressed. The hippocampus, for instance, a center for learning and memory, is often shrunk in depression, perhaps because it is damaged by the stress hormone, cortisol. Some scientists also think the amygdala, a fear processing center, may be involved.

And other subregions seem to play a role too. Mayberg, for instance, asks volunteers to recall a sad memory. When they start crying, she uses a PET scan to measure blood flow in the brain. The "hottest" area (the one with the biggest increase in blood flow) turns out to be a small part of the anterior cingulate called area 25, part of the limbic system. While this area gets more active, the prefrontal cortex, or thinking area, turns off.

In healthy people immersed in sad feelings, the brain can quickly shift back toward equilibrium. "The phone rings, the baby cries, the boss calls and you immediately disengage from the sadness and the thinking part of the brain turns back on," she says. With depressed people, this ability to shift back to equilibrium is altered.

That may be because area 25 has direct links to area 24a, a monitoring center for emotions. In some depressed people, area 24a is virtually stuck in the "on" position, which may reflect the brain's frantic attempt to handle upsetting feelings, Mayberg says. But that may be a good sign. Depressed people with high activity in area 24a typically get better with drug treatment; those with low activity in 24a don't.

While PET scans like the ones Mayberg uses can detect changes deep in the brain, Dr. Andrew Leuchter at UCLA has found that he can predict which patients will respond to drugs with a simpler tool. Using a system called QEEG (for quantitative EEG), Leuchter studies depressed people with low activity in the prefrontal lobes. Then he looks at what happens when they start taking Prozac, which typically takes six weeks to improve mood.

In the first few days, some people show a further decrease in prefrontal lobe activity, particularly in the area closest to the eyes, followed about a week later, by an increase. But some people don't show this initial decline. When Leuchter follows the patients over time, the ones who respond best to drugs are those who show the initial decline. "Once somebody has started on medication, we can see whether they will respond in under a week," he says.

Eventually, this should enable doctors to tell people who are likely to improve on a drug to be patient because their "brain changes are on the right track." Those deemed unlikely to respond to a given drug can be given other drugs.

Depressed Rats and the Forced Swim Test

And then there are the lessons to be learned from depressed rats. Researchers who study depression in lab animals use a behavioral test called the "forced swim test." It works like this: Normal rats are put in a tub of water. Typically, they swim hard for 10 minutes, then give up and float until researchers take them out. The next day, they are put back in the water, whereupon they give up much faster, usually after 2 minutes. This, researchers say, illustrates the "learned helplessness" model of depression. If they are given Prozac, rats (unlike people) seem to experience an immediate benefit--they don't stop swimming nearly as fast on the second day. "Every depression treatment known to man--all drugs, electroshock therapy, TMS--all affect the forced swim test," says McLean neurobiologist William Carlezon.

In a recent paper in Journal of Neuroscience, Carlezon showed that there are other ways to keep rats swimming longer and, presumably, feeling good. The team focused on a protein called CREB, which activates a gene that makes dynorphin. A close cousin of endorphins and enkephalins, dynorphin is a natural painkiller. But unlike its cousins, it makes people feel "lousy, not euphoric," says Carlezon.

Carlezon used injections into an area of the brain called the nucleus accumbens to increase or decrease levels of CREB, and therefore dynorphin. When the rats had too much CREB, they gave up on the swim test after only one minute, suggesting that they were indeed depressed. When the researchers blocked CREB, the rats swam like champs, or more precisely, like rats on Prozac. The rats also swam a long time when given drugs that directly block dynorphin.

CREB, in other words, "is a molecular trigger for depression that acts by increasing dynorphin," says Carlezon. That suggests that drugs that fight depression faster than Prozac might be developed for humans, though so far no known dynorphin-blockers can enter the human brain.

Precisely how all these new pieces of the depression puzzle fit together remains a mystery. But it's clear that not only is depression not a character flaw, it's not even biochemically as simple as once thought.

"As we understand better the fundamental causes of depression," says Dr. Scott Ewing, director of the depression and anxiety clinic at McLean, "we can expect to see over the next decade antidepressants developed that will be more effective and more rapidly acting."